Succinate semi-aldehyde dehydrogenase deficiency

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Classification according to ICD-10
E72.8 Other specified disorders of amino acid metabolism
ICD-10 online (WHO version 2019)

Succinate semi-aldehyde dehydrogenase deficiency ( English succinic semialdehyde dehydrogenase deficiency, SSADHD ) is an extremely rare congenital metabolic disorder . It is characterized by a deficiency in the enzyme that is involved in the breakdown of gamma-aminobutyric acid (GABA). GABA is one of the most important inhibitory neurotransmitters in the brain and controls human movements; an imbalance leads to neurological abnormalities. With an SSADH deficiency, the signal transmission by neurotransmitters is disturbed. The metabolic disorder falls under the neurotransmitter diseases.

"Neurotransmitter disease" is a generic term for genetic disorders that affect the synthesis, metabolism and breakdown of neurotransmitters. These innate metabolic disorders affect the central nervous system and if left untreated, neurological function can be severely impaired.

Synonyms are: succinic acid semialdehyde dehydrogenase deficiency; Succinate semialdehyde dehydrogenase deficiency; 4-hydroxybutyraziduria; 4-hydroxybutyric aciduria

distribution

The frequency of occurrence of an SSADH deficiency is given as less than 1 in 1,000,000. In the literature about 450 diagnosed cases worldwide are mentioned, it is assumed, however, that many SSADH patients are either not diagnosed or are incorrectly diagnosed and thus the number of unreported cases is probably considerably higher.

Inheritance is autosomal - recessive . Recessive disorders only manifest when a person inherits the same defective gene from each parent. A child who has a normal gene and a “sick” gene is a carrier but does not show any symptoms. As for any recessive inherited disorder, the likelihood of transmitting the disease to the children of a couple when both parents are carriers is 25 percent. Statistically, 50 percent of their children can be carriers of the disease, and 25 percent can both receive normal genes. The risk is the same for every pregnancy. SSADH deficiency affects men and women equally.

root cause

The disease is based on mutations in the ALDH5A1 gene at locus 6p22.3. The enzyme SSADH is involved in the breakdown of γ-aminobutyric acid (GABA), γ-hydroxybutyric acid (GHB) and 4-hydroxynonenal (HNE). Mutation-related functional impairments of the enzyme result in an increase in the physiological level of these substances. GHB is a neurotransmitter and modulator . HNE is an electrophile that causes oxidative stress and is toxic.

Symptoms

Symptoms associated with SSADH deficiency can be mild, moderate, or severe and often vary widely from case to case. Manifestations can include:

  • Delayed development of gross and / or fine motor skills
  • Mental development retarded
  • Delayed language development
  • Hypotension

Diagnosis and treatment

SSADH deficiency is diagnosed by profiling organic acids in urine or analyzing amino acids in the blood.

There is currently no known established and generally effective therapeutic treatment for SSADH deficiency. In the longer term, medical advances in gene therapy or stem cell transplantation could be ways to cure the disorder in the future. In the short term, various therapies have been investigated so far:

history

The disease was first described in 1981 by the Dutch pediatrician Cornells Jakobs et al .

literature

  • M. Gahr, BJ Connemann, CJ Schönfeldt-Lecuona, RW Freudenmann: Succinate-semialdehyde-dehydrogenase deficiency: an inheritable neurometabolic disease. In: Advances in neurological psychiatry. Volume 81, No. 3, March 2013, pp. 154-161, doi: 10.1055 / s-0032-1330544 . PMID 23516105 (Review).

Web links

Individual evidence

  1. ^ National Council for Health and Welfare in Sweden: Rare diseases - Succinic semialdehyde dehydrogenase deficiency.
  2. ↑ 4-Hydroxybutyraziduria. In: Orphanet (Rare Disease Database).
  3. ↑ Succinic semialdehyde dehydrogenase deficiency.  In: Online Mendelian Inheritance in Man . (English)
  4. ↑ P. Malaspina, MJ Picklo, C. Jakobs, OC Snead, KM Gibson: Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency. In: Human Genomics. 106, 2009. PMID 19164088
  5. ↑ C. Jakobs, M. Bojasch, E. Mönch, D. Rating, H. Siemes, F. Hanefeld: Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. In: Clinica Chimica Acta . Vol. 111, No. 2-3, April 1981, pp. 169-178. PMID 7226548 .